Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells

Peng H Tan; Pervinder Sagoo; Cliburn Chan; John B Yates; Jamie Campbell; Sven C Beutelspacher; Brian M J Foxwell; Giovanna Lombardi; Andrew J T George

doi:10.4049/jimmunol.174.12.7633

Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells

J Immunol. 2005 Jun 15;174(12):7633-44. doi: 10.4049/jimmunol.174.12.7633.

Authors

Peng H Tan¹, Pervinder Sagoo, Cliburn Chan, John B Yates, Jamie Campbell, Sven C Beutelspacher, Brian M J Foxwell, Giovanna Lombardi, Andrew J T George

Affiliation

¹ Department of Immunology, Division of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.

PMID: 15944264
DOI: 10.4049/jimmunol.174.12.7633

Abstract

Dendritic cells (DCs) are central to T cell immunity, and many strategies have been used to manipulate DCs to modify immune responses. We investigated the effects of antioxidants ascorbate (vitamin C) and alpha-tocopherol (vitamin E) on DC phenotype and function. Vitamins C and E are both antioxidants, and concurrent use results in a nonadditive activity. We have demonstrated that DC treated with these antioxidants are resistant to phenotypic and functional changes following stimulation with proinflammatory cytokines. Following treatment, the levels of intracellular oxygen radical species were reduced, and the protein kinase RNA-regulated, eukaryotic translation initiation factor 2alpha, NF-kappaB, protein kinase C, and p38 MAPK pathways could not be activated following inflammatory agent stimulation. We went on to show that allogeneic T cells (including CD4(+)CD45RO, CD4(+)CD45RA, and CD4(+)CD25(-) subsets) were anergized following exposure to vitamin-treated DCs, and secreted higher levels of Th2 cytokines and IL-10 than cells incubated with control DCs. These anergic T cells act as regulatory T cells in a contact-dependent manner that is not dependent on IL-4, IL-5, IL-10, IL-13, and TGF-beta. These data indicate that vitamin C- and E-treated DC might be useful for the induction of tolerance to allo- or autoantigens.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Antioxidants / pharmacology*
Apoptosis / drug effects
Apoptosis / immunology
Ascorbic Acid / pharmacology*
Cell Differentiation / immunology
Cells, Cultured
Clonal Anergy / drug effects
Clonal Anergy / immunology
Dendritic Cells / drug effects
Dendritic Cells / immunology*
Dendritic Cells / metabolism*
Dexamethasone / pharmacology
Down-Regulation / drug effects
Down-Regulation / immunology
Drug Combinations
Humans
Immunophenotyping
Intracellular Fluid / immunology
Intracellular Fluid / metabolism
NF-kappa B / antagonists & inhibitors*
NF-kappa B / physiology
Oxidation-Reduction / drug effects
Protein Kinase C / antagonists & inhibitors
Protein Kinase C / physiology
Reactive Oxygen Species / antagonists & inhibitors
Reactive Oxygen Species / metabolism
Signal Transduction / drug effects
Signal Transduction / immunology*
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism
alpha-Tocopherol / pharmacology*
eIF-2 Kinase / antagonists & inhibitors
eIF-2 Kinase / physiology
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases / physiology

Substances

Antioxidants
Drug Combinations
NF-kappa B
Reactive Oxygen Species
Dexamethasone
eIF-2 Kinase
Protein Kinase C
p38 Mitogen-Activated Protein Kinases
alpha-Tocopherol
Ascorbic Acid